Savient Shares Tumble on Safety Data from Extension

BioWorld Today Science Editor

Shares of Savient Pharmaceuticals Inc. tumbled 73.5 percent Monday after the company presented data on its pegloticase (Puricase) for treatment-resistant gout. Even though the drug has met its endpoint in two Phase III studies, analysts were skeptical about a key safety issue, its prospects for approval, and the size of its market if it is approved.

Gout is a form of arthritis caused by an accumulation of uric acid in the joints that can result from making too much urea, or not metabolizing it properly. More than 1 million Americans have a gout attack each year, most of them males older than 40.

In data unveiled at the American College of Rheumatology, researchers presented data on two Phase III studies, GOUT1 and GOUT2. Topline results of both studies were first presented late last year. In both studies, the drug hit its endpoint, normalizing plasma uric acid levels during month 3 and month 6 of the trials. (See BioWorld Today, Dec. 14, 2007.)

New data presented at ACR showed that gout flares - acute gout attacks - decreased by about 40 percent in patients receiving pegloticase every two weeks compared to those receiving placebo. Gout tophi - deposits of crystallized uric acid in soft tissue - showed a complete response in patients receiving pegloticase every two weeks, as well as in the pooled response from patients receiving the drug every two weeks and every four weeks. But the third time was the charm for Puricase. The data included an uncontrolled open-label extension study known as GOUT 3 that failed to convince analysts of the drug's prospects.

The company's take on the data was positive: In a press release, Savient described the results as showing that "a substantial subset of patients who completed the Phase III clinical trials and enrolled in the [open-label extension] continued to show improvements in the resolution of their signs and symptoms of treatment-failure gout with continuing pegloticase treatment, extending the positive clinical results seen in Phase III. The two clinical efficacy endpoints of most interest, gout flares and gout tophi, showed an increasing proportion of patients with favorable response over time."

The East Brunswick, N.J.-based company said that the drug has "an acceptable safety and tolerability profile" when administered every two or every four weeks, and that "the emerging safety profile of long-term pegloticase therapy is consistent with that observed in the six double-blind studies, with no apparent new safety concerns related to long-term exposure."

On this point, however, some analysts disagreed.

Rachel McMinn of Cowen & Co. wrote in a note that "The surprising new information for investors is that Puricase in Phase III was associated with cardiovascular adverse events in 5 percent of patients vs. 0 percent for placebo patients."

Savient itself reported one cardiovascular death in the placebo group, but that patient died before receiving any placebo. Both Cowen, which downgraded Savient on Monday, and Jeffries & Co., which lowered its price target on the company, cited the higher rate of cardiac adverse events in the treatment group as cause for concern.

Analysts also said it is unlikely that pegloticase will win FDA approval on its first attempt, given that the company said it plans to file a biologics licensing application by the end of this month and expects approval in the first half of 2009. But Cowen's report cited a "lack of conviction" that pegloticase will receive first-pass FDA approval as one reason for the downgrade. Cowen noted that cardiovascular events as well as adverse infusion reactions, including anaphylactic shock-like reactions, "complicate the risk-reward profile of the drug."

And Jefferies and Co. noted that trouble could await from "an overly cautious FDA," particularly its division of anesthesia, analgesia and rheumatology, which was burned by the Vioxx episode.

Credit Suisse analysts, however, were more positive, saying that because of the small size of the study, 4:1 randomization, and patient comorbidities, it is impossible to ascertain any statistically significant imbalance.

One dual-edged sword for the company is that its drug is aimed at treatment-refractory patients who have exhausted other treatment options and are, on the average, very ill. While that makes side effects more acceptable than with a milder disease, it also means that the potential market is fairly small - another reason cited by analysts for their skepticism. Savient will present further data on the immune response of patients receiving long-term treatment with pegloticase at the conference tomorrow, and will conduct a conference call on Wednesday.

Shares of Savient (NASDAQ:SVNT) dropped $8.51, to close at $3.07.

Savient wasn't the only company presenting gout data at the ACR. San Diego-based Ardea Biosciences presented Phase I data at the meeting showing that its RDEA594, for hyperuricemia and gout, showed what the company termed "a favorable pharmacokinetic profile with low systemic clearance, favorable absorption and a half-life supporting once-daily dosing." 100 mg daily of the drug also significantly increased the excretion of uric acid.

And Xoma, Inc., of Berkeley, Calif., presented data showing that its XOMA052 blocks inflammation in a mouse model of gout.

The following data were presented at the American College of Rheumatology Annual Scientific Meeting in San Francisco.

 Amgen Inc., of Thousand Oaks, Calif., and Wyeth Pharmaceuticals, a division of Wyeth, of Madison, N.J., said Enbrel (etanercept) has shown sustained improvements in multiple measures of efficacy in moderate to severe rheumatoid arthritis (RA) patients completing up to 10 years of therapy. Approximately one-third of patients who started either of two studies continued on Enbrel throughout the decade. Of patients evaluated for efficacy and still on therapy for up to 10 years, 56 percent achieved an ACR 50 response. Also, 39 percent and 31 percent (ERA and LRA, respectively) achieved an ACR 70 response. Those scores represent a 50 percent or 70 percent improvement in RA outcome measures that include joint swelling and tenderness, pain, level of disability, overall patient and physician disease assessment, and an objective marker of inflammation. Separately, new safety and efficacy data for active ankylosing spondylitis patients treated with Enbrel showed that it was effective in treating the signs and symptoms of active AS in significantly more patients than those receiving sulphasalazine, a disease-modifying antirheumatic drug, and significant differences were reported as early as two weeks.

 Centocor Inc., of Horsham, Pa., said results from two Phase III studies showed that patients receiving every four week subcutaneous injections of golimumab (CNTO 148) 50 mg or 100 mg experienced significant improvements in physical function, health-related quality of life and fatigue. The data from the randomized, double-blind, placebo-controlled studies in patients with active moderate to severe rheumatoid arthritis (RA) showed golimumab-treated patients who had discontinued previous anti-TNF treatment for any reason experienced significant improvements in physical function, as measured by the Health Assessment Questionnaire (HAQ). At week 24, the proportion of patients experiencing clinically relevant improvement was significantly greater for golimumab-treated patients compared with those receiving placebo. More than half of patients in the combined golimumab group (52 percent) achieved the measure, compared with 34 percent of placebo-treated patients (P < 0.001). Also at week 24, patients receiving golimumab experienced a mean improvement in HAQ of 0.27 +/- 0.51, compared with an improvement of 0.05 +/- 0.51 among patients receiving placebo (P < 0.001). Among patients whose prior anti-TNF therapy was discontinued due to lack of efficacy, golimumab-treated patients experienced a mean improvement of 0.23 +/- 0.50 in HAQ, compared with an average improvement of 0.06 +/- 0.51 for patients receiving placebo (P < 0.05). Separately presented data showed more than half of patients receiving every four week subcutaneous injections of golimumab 50 mg and 100 mg experienced sustained improvements in the joint and skin symptoms of active psoriatic arthritis through six months with results sustained through one year.

 CombinatoRx Inc., of Cambridge, Mass., reported an in-depth analysis from its Phase IIb trial (COMET-1) designed to evaluate the safety and efficacy of Synavive (CRx-102) in subjects with symptomatic knee osteoarthritis (OA). The analysis has included a modified intent-to-treat (mITT) population, which accounts for subjects who stopped taking their blinded study drug (placebo or active) and commenced use of a prohibited medication (such as an NSAID or COX-2 inhibitor) prior to their end-of-study visit. In the mITT analysis, high-dose Synavive provided treatment benefits compared to placebo and prednisolone, across a range of efficacy measures, including WOMAC pain, stiffness and physical function subscales.

 Genentech Inc., of South San Francisco, and Biogen Idec Inc., of Cambridge, Mass., said Rituxan (rituximab) in two separate Phase III studies, significantly improved ACR20 scores in biologic-naive RA patients who inadequately responded methotrexate (MTX), and in those moderately-to-severely active RA patients who had an inadequate response to previous treatment with at least one TNF inhibitor. A different Phase II study showed that patients receiving Rituxan in combination with MTX elicited comparable immune response to tetanus vaccines to those receiving placebo plus MTX.

 Hoffmann-La Roche Inc., of Nutley, N.J., said data from two Phase III studies showed that rheumatoid arthritis patients achieved significant improvements in signs and symptoms when treated with Actemra (tocilizumab) alone or in combination with methotrexate compared with methotrexate alone. Results of the RADIATE study involving difficult-to-treat patients who failed to respond to prior anti-tumor necrosis factor-alpha therapies demonstrated that half of patients treated with Actemra (8 mg/kg) in combination with methotrexate achieved a 20 percent reduction (ACR20)(1) in RA signs and symptoms, compared with 10 percent of patients treated with methotrexate alone.

 Incyte Corp., of Wilmington, Del., reported results from a 28-day Phase IIa trial showing that its orally available janus kinase (JAK) inhibitor INCB18424 produced impressive clinical benefits and all of the doses were well tolerated in rheumatoid arthritis patients. American College of Rheumatology (ACR) 20, ACR50, ACR70 and ACR90 response rates in the three most effective dose groups were achieved in one month, with responses seen as early as one week. Based on these results, two six-month Phase IIb trials using a similar range of doses are expected to begin in the fourth quarter of this year

 Lexicon Pharmaceuticals Inc., of The Woodlands, Texas, presented results from a recently completed Phase 1b multiple ascending-dose trial, and showed that LX2931 was well tolerated at all doses over the seven-day dosing period, and produced a dose-dependent reduction in circulating lymphocytes, with rapid recovery following discontinuation of dosing. Lexicon is planning to progress LX2931 into a drug-drug interaction study in rheumatoid arthritis patients who are also taking methotrexate, a standard therapy.

 Targeted Genetics Corp., of Seattle, announced positive results of its Phase I/II study showing that tgAAC94, an investigational agent designed to inhibit activity of tumor necrosis factor-alpha, is well tolerated and may improve disease symptoms in inflammatory arthritis patients. In the study, 127 patients with inflammatory arthritis received a single intra-articular injection of either tgAAC94 or placebo, followed by a second injection 12-30 weeks later depending on when the injected joint met criteria for re-injection. TgAAC94 was well tolerated at all dose levels. Two SAEs of focused interest were reported - a culture-negative septic arthritis considered probably related to study drug and a fatal disseminated histoplasmosis and retroperitoneal hemorrhage considered not related to study agent. Administration site reactions were observed in 12 percent of subjects. Preliminary signs of efficacy were also observed in the study, most notably a 30 percent decrease in patient-reported pain and functional scores. Shares of Targeted Genetics (NASDAQ:TGEN) rose 6 cents, or 25 percent, to close at 30 cents.

 Trubion Pharmaceuticals Inc., of Seattle, said TRU-015 in a Phase I/IIa trial is well tolerated and demonstrated maintenance of ACR responses following administration of a single dose of TRU-015 at six-month intervals along with B-cell depletion and recovery following retreatment, comparable to results seen after initial treatment, for two years. A Phase IIb trial to evaluate safety, tolerability and pharmacodynamics of TRU-015 in RA patients following initial administration, is ongoing. TRU-015 is being developed by Wyeth Pharmaceuticals, a division of Wyeth, of Madison, N.J., in collaboration with Trubion.

 UCB SA, of Brussels, Belgium, reported results from several Phase III trials evaluating Cimzia (certolizumab pegol), its pegylated anti-TNF (Tumor Necrosis Factor), in rheumatoid arthritis. The results showed that Cimzia, either as monotherapy or combined with standard therapy methotrexate, provides significant rapid relief with patients achieving American College of Rheumatology 20 response as early as one week, compared to placebo. Cimzia also provides sustained relief from RA for up to two years.